A device containing an immobilized chelator to remove aluminum from total parente

描述（由申请人提供）：在美国，每年约有50万名早产儿需要静脉喂养，因为他们不能耐受口服喂养。这是通过全胃肠外营养（TPN）溶液来实现的，TPN溶液由以下组分溶液制备：小体积和大体积胃肠外（SVP和LVP）。铝（Al）是某些SVP中的常见污染物，特别是葡萄糖酸钙溶液。过量的铝会对骨骼系统和大脑产生毒性，也许还有肝脏。铝毒性的潜力是显着更大的人，如早产儿，谁有肾功能下降，因为肾脏排泄铝。医疗人员谁照顾新生儿建议了几十年，这些解决方案中的铝需要大大减少，以避免铝诱导的毒性。FDA对这些组分溶液实施了标签要求，设定了LVP中的最大铝浓度，并要求在失效时声明SVP中的最大铝浓度。这仅记录了估计的最大Al浓度。这不是实际的铝浓度，也不会减少SVP中的铝。基于开发结合Al的新化学品（螯合剂）的先前工作，长期目标是开发含有螯合剂的流通式过滤器装置，所述螯合剂固定在小聚合物珠上以从溶液中除去Al。基于使用计算化学获得的结果，其预测了新型固定化螯合剂与Al的结合强度，以及在我们合成的新型螯合剂的第一阶段奖励之前和期间获得的结果，提出了改进先导树脂（固定在树脂珠上的螯合剂），并开发含有铅树脂的原型装置，并测试这些装置从葡萄糖酸钙溶液中去除铝的有效性和安全性。然后，我们将在接受TPN的新生儿的临床前原理证明仔猪模型中评估所得优化器械的安全性和有效性。结果将使该项目进入III期，其中树脂和器械将在cGMP条件下生产，器械将在新生儿重症监护室接受TPN的新生儿中进行临床原理验证研究。 公共卫生相关性：拟议的工作将推进铅树脂（固定化螯合剂），并开发和测试包含树脂的原型设备，以创建一种医疗设备，从静脉注射溶液中去除有毒污染物铝（Al）。该器械将在接受静脉喂养的新生儿动物模型中进行临床前原理验证研究。这将消除铝对早产儿和其他通过静脉注射暴露于铝的患者产生毒性的可能性，解决了一个数十年来一直未能解决的问题。

DESCRIPTION (provided by applicant): A high percentage of the ~ 500,000 children born prematurely each year in the US require intravenous feeding after birth because they do not tolerate oral feeding. This is accomplished with a total parenteral nutrition (TPN) solution, which is prepared from component solutions: small and large volume parenterals (SVPs and LVPs). Aluminum (Al) is a common contaminant in some SVPs, particularly calcium gluconate solution. Excessive Al can produce toxicity to the skeletal system and brain, and perhaps the liver. The potential for Al toxicity is significantly greater in humans, such as premature infants, who have reduced renal function; because the kidneys excrete Al. Medical personnel who care for neonates have suggested for decades that the Al in these solutions needs to be greatly decreased to avoid Al-induced toxicity. The FDA implemented a labeling requirement for these component solutions that sets a maximum Al concentration in LVPs and requires a statement of the maximum Al concentration in SVPs at expiry. This merely documents estimated maximum Al concentration. It is not the actual Al concentration nor does this reduce the Al in SVPs. Based on prior work to develop new chemicals that bind Al (chelators), the long- term objective is to develop a flow-through filter device containing a chelator that is immobilized on small polymer beads to remove Al from solutions. Based on results obtained using computational chemistry, which predicted the strength of binding of novel immobilized chelators with Al, and results obtained before and during the Phase I award from novel chelators we have synthesized, it is proposed to advance the lead resin (a chelator immobilized on a resin bead), and develop prototype devices containing the lead resin, and test these devices for their efficacy to remove Al from calcium gluconate solution and their safety. We will then assess the safety and efficacy of the resultant optimized device in a pre-clinical proof- of-principle piglet model of the neonate, receiving TPN. The results will position this project to advance to Phase III, in which the resin and device will be manufactured under cGMP conditions and the device tested in a clinical proof-of-principle study in neonates receiving TPN in a neonatal intensive care unit. PUBLIC HEALTH RELEVANCE: The proposed work will advance the lead resin (immobilized chelator) and develop and test prototype devices to contain the resin, to create a medical device to remove a toxic contaminant, aluminum (Al), from intravenous solutions. This device will be tested in a pre- clinical proof-of-principle study in an animal model of the neonate receiving intravenous feeding. This will remove the potential for Al to produce toxicity to premature infants and other patients who are exposed to Al through intravenous fluids, solving a decades-old problem that has escaped resolution to date.